Development Stage: The biomarker was evaluated in 1581 primary tumor tissue samples from node-positive operable breast cancer patients who participated in a randomized clinical trial

Novelty: AKT phosphorylation at Ser473 (pAKT) has been identified as a biomarker that predicts treatment benefit from sequential addition of a taxane (paclitaxel or docetaxel) to doxorubicin and cyclophasphomide (AC) chemotherapy to assist physicians in making treatment decisions for high-risk and node-positive breast cancer patients

Clinical Application: Identification of patients by examining pAKT expression status in pre-treatment surgical tumor specimens or tumor biopsies to receive a taxane if patients have pAKT-positive tumors or spare a taxane if patients have pAKT-negative tumors

General Description Taxanes are a class of compounds widely used as chemotherapeutics in the treatment of various cancers including breast, lung, ovarian cancer, prostate, cervical cancer, testicular cancer, Kaposi’s sarcoma and non-hodgkin’s lymphoma. Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere) and are effective in many patients, however, not all patients benefit from this type of chemotherapy. Due to the negative side effects associated with the use of most chemotherapies, including taxanes, there is a significant need for a means of predicting clinical outcome from taxane-based chemotherapy to avoid subjecting patients that will not benefit from the drug to unnecessary side effects. Both paclitaxel and docetaxel are known to function as mitotic inhibitors which disrupt the microtubules that pull the cell apart when it divides. Akt, also known as protein kinase B, is a serine/threonine kinase that is involved in cellular survival pathways by inhibiting apoptosis. Phosphorylation of Akt and the associated downstream events play a critical role in these pathways. Paclitaxel and docetaxel both assert their activity by inhibiting Akt-Ser473 phosphorylation (pAkt) and induces mitotic arrest. Taxanes may cause more damage to tumor cells that are dependent on pAkt for survival and cell cycle progression, significantly impacting treatment outcomeScientific Progress Researchers at NCI have identified pAkt as having predictive significance for paclitaxel chemotherapy outcome in patients with early stage breast cancer. The researchers have developed an immunohistochemistry method for determining pAkt status with appropriate controls for assay performance and cutoff for pAkt positivity. They also discovered methods of correlating pAkt expression with clinical outcome (disease-free survival and overall survival). Primary tumors from patients in a clinical trial who were randomly assigned to receive either four cycles of cyclophosphamide (AC) chemotherapy alone or followed by four cycles of paclitaxel were evaluated with this method with researchers blinded to clinical outcome. A total of 1581 tumor samples were used in this evaluation. Of the 1581, 975 had pAkt-negative tumors and 606 had pAkt-positive tumors. For the 975 patients with pAkt-negative tumors there were no differences observed in disease-free survival (adjusted hazard ratio [HR], 1.02; P = 0.81) or overall survival (HR, 0.97, P = 0.80) with or without receiving paclitaxel. However, in the 606 patients with Akt-positive tumors, the addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = 0.02) and a 20% improvement in overall survival (HR, 0.80; P = 0.17). This data suggests that pAkt is a novel predictive marker of taxane-based chemotherapy, and could be applied to indicate which patients should receive taxane-based chemotherapyFuture Plans

The inventors future plans are to test pAKT on taxane benefit in neoadjuvant and metastatic settings in breast cancer; examine pAKT on predicting taxane benefit in lung, ovarian cancer, prostate, cervical, and testicular cancers, as well as Kaposi’s sarcoma and non-hodgkin’s lymphoma

Only tested AC and paclitaxel (standard of care) in adjuvant setting for early stage breast cancer, could extend to taxane-based chemotherapy in metastatic setting for breast cancer and other types of cancer in adjuvant, neoadjuvant and metastatic settings to determine broad applicability

Sandra Swain, MD, FACP is the medical director of MedStar Washington Hospital Center’s Washington Cancer Institute, a professor in the department of medicine at Georgetown University, and the Immediate Past President of the American Society of Clinical Oncology (ASCO). Dr. Swain has an international reputation as a leading authority both in the field of inflammatory breast cancer treatment and in the treatment of early breast cancer. Her research interests include targeted therapy for advanced breast cancer, inflammatory breast cancer, and adjuvant therapy. She has designed, implemented, and published more than 30 clinical trials serving as Principal Investigator on a regional and international level. She has published over 220 articles. Throughout her career, Dr. Swain has also served in leadership and advisory roles for many fellows and several professional oncology organizations, and is also the recipient of many clinical, academic and research oriented awards.